The average U.S. adult consumes nearly 10 g of salt per day, far in excess of the limit recommended by the Departments of Agriculture and Health and Human Services.1,2 High salt intake has been linked to hypertension and cardiovascular disease.3,4 Randomized clinical trials demonstrate that reducing salt intake substantially lowers this risk.5 It has been estimated that a 3 g reduction of daily salt intake would save an estimated 44,000 to 92,000 lives annually in the U.S.6 
The natriuretic peptide system plays a central role in the response to salt intake. Synthesized by the heart, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) promote natriuresis, diuresis, and vasodilation. In animals, deficient ANP signaling results in salt-sensitive hypertension, adverse cardiac remodeling, and premature mortality.7,8 Evidence from population genetic studies suggests that variation in plasma natriuretic peptides may alter susceptibility to cardiovascular disease in humans as well. Common genetic polymorphisms in the chromosome 1 region containing NPPA and NPPB, which encode the ANP and BNP propeptides, respectively, are associated with circulating natriuretic peptide levels.9 Large-scale epidemiologic studies have established that the same variants are associated with blood pressure with, for example, a 15% lower risk of hypertension in carriers of the rs5068 minor allele.9,10 
Genetic studies have appeal because they avoid the reverse causation that can be observed with non-genetic associations. However, as with all complex traits, the majority of blood pressure-related variants are non-coding, and there are typically many partially correlated variants due to linkage disequilibrium. These factors increase the difficulty of identifying a causal variant and the mechanism by which it acts. Indeed, although genome-wide association studies (GWASs) have yielded a long list of candidate single nucleotide polymorphisms (SNPs) for blood pressure, the only genetic variants, for which a mechanism has been established, are rare mutations in families with Mendelian forms of hypertension or hypotension.11 
More than 30% of adults in the US have hypertension, and hypertension is an important risk factor for myocardial infarction, stroke, and heart failure (Go, et al., Circulation 127:143-152.5). Seventy-five percent of adults with hypertension are taking antihypertensive medications, but target blood pressures are attained in only 53%. It is estimated that, in 2010, ˜3% of Americans over the age of 18 had heart failure, and about 50% of patients diagnosed with heart failure die within 5 years (Roger et al., Circulation 125:e2-e2206). The 2010 health care costs associated with treating hypertension and heart failure (including those related to lost productivity) were estimated to be 93.5 and 34.4 billion dollars, respectively (Heidenreich, et al., Circulation 123:933-944.). These data strongly indicate that it is necessary to elucidate the mechanisms responsible for hypertension and demonstrate the need to develop novel treatment strategies for the effective treatment of hypertension and heart failure (HF).